Fibrosis of tissue accompanying deposition of collagenous fiber is a phenomenon that occurs during wound healing process in the body as a terminal state of an inflammation reaction, and plays an important role in wound healing and the like in the body. On the other hand, excessive fibrosis of tissue is considered an onset or aggravating factor of various diseases based on inflammation, for example, dermatic disease, cardiac disease, respiratory disease, autoimmune disease, collagen disease, cancer, arteriosclerosis, diabetes and the like. Moreover, the mechanism of fibrosis has not been sufficiently elucidated, and the treatment of these diseases accompanying fibrosis is difficult.
Scleroderma (systemic scleroderma) which is one of the collagen diseases, is a disease mainly comprising enhanced synthesis and accumulation of collagenous fiber in the skin and internal organs. The disease characteristically shows a male-to-female ratio of about 1:9, and occurs in many females in the middle age of 30-50 years old. The pathology thereof also includes skin lesions such as Raynaud's symptoms, skin hardening and the like, as well as internal organ diseases such as lung fibrosis, renopathy, reflux oesophagitis and the like. Therefore, scleroderma is an intractable disease that affects not only the quality of life but also life prognosis, and at present, an effective treatment method and the like have not been established.
Conventionally, an animal model used for fibrosis, particularly, scleroderma, is a mouse having an artificially-developed fibrosis by the administration of drugs such as bleomycin and the like, cytokines such as TGFβ (transforming growth factor beta), CTGF (connective tissue growth factor), bFGF (basic fibroblast growth factor) and the like (non-patent documents 1, 2), or Tight skin mouse having gene abnormality at Fibrillin-1 (non-patent documents 3, 4). However, these known animal models have problems since, when, for example, a mouse is administered with cytokine in the skin, the skin of the administration site is only topically hardened, Tight skin mouse shows skin hardening of the equivalent level for male and female, and renopathy, reflux oesophagitis and the like are not observed, and the like. Therefore, all known animal scleroderma models are not sufficient in terms of the similarity to the pathology in human, artificiality and the like. Moreover, since Fibrillin-1 was reported to be a responsible gene of Stiff Skin Syndrome, which is a genetic disease completely different from scleroderma (non-patent document 5) in recent years, usefulness of tight skin mouse as a scleroderma model mouse has been questioned.